tbuckley/cabot-search huggingface dataset:
A phase I/II dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC) in patients with prior treatment with 177Lu-PSMA.
Authors: Jones T. Nauseef, Michael Philip Sun, Charlene Thomas, Mahelia Bissassar, Amie Patel, Angela Tan, Escarleth Fernandez, Zachary Davidson, Tessa Chamberlain, Kara Earle, Rebecca Wunder, Sandra Huicochea Castellanos, Peter Gregos, Joseph Osborne, Karla V. Ballman, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil Harrison Bander, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2023)

TPS288 Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based targeting (e.g., J591) and potent alpha emitting payloads (e.g., 225Ac) impact drug kinetics, biodistribution, and resultant clinical toxicities. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg without achievement of maximal tolerated dose (MTD). One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of Gr 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had Gr &gt; 3 heme toxicity or Gr &gt; 2 non-heme toxicity. Although not intentionally preselected for prior exposure, 55% (12/22) of patients had 177Lu-PSMA previously. With approval of 177Lu vipivotide tetraxetan, we amended an ongoing phase I dose-escalation study to include a post-177-Lu-PSMA cohort. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function, and prior receipt of AR pathway inhibitor and chemotherapy (or refused/ineligible). There is no limit to prior lines of therapy except alpha-emitting therapies (i.e., PSMA-TRT, 223Ra) and in this amended dose-escalation cohort, all patients must have had prior treatment with 177Lu-PSMA. Treatment will be given in a single fractionated cycle of 225Ac-J591 administered on D1 and D15. The phase I component is a 3+3 dose-escalation study design with up to 18 patients, with the goal of identifying MTD. The phase II component will include up to 16-19 patients in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG3-modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment to the post-177Lu-PSMA cohort began in August 2022. Clinical trial information: NCT04506567 .
Therapeutic potential of plant-derived nanovesicles for neuroendocrine prostate cancer.
Authors: Sharanjot Saini, Amritha Sreekumar, Tae Jin Lee, Ashok Sharma, Matthew Simmons
Journal: Journal of Clinical Oncology (2023)

186 Background: Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of prostate cancer (PCa) that often emerges after androgen receptor (AR)-targeted therapies such as enzalutamide and abiraterone. NEPC arises via trans-differentiation of prostate adenocarcinomas to neuronal lineage, a process referred to as ‘neuroendocrine trans-differentiation’ (NED), wherein prostate cancer cells show an altered expression of lineage markers such as decreased expression of AR and increased expression of neuronal markers. Currently, there is a lack of effective targeted therapies for NEPC. Current treatment options are limited to highly toxic platinum-based drugs. Hence, there is an urgent need to develop novel treatment strategies to treat NEPC. The focused objective of this study is to develop novel, non-toxic therapeutic intervention against NEPC. Towards this, we exploited the potential of plant-derived nanovesicles/extracellular vesicles as a novel therapeutic. Extracellular vesicles (EVs) are lipid-bilayer-delimited particles that are released from almost all types of cells, including plant cells, typically between 30-150 nm in size. Methods: EVs/nanovesicles were isolated from plant-derived sources by ultracentrifugation. Isolated nanovesicles were characterized by Nanoparticle Tracking Analyses and electron microscopy. After characterization, the effects of nanovesicles were tested in NEPC cell lines in vitro. Effects on cell viability and apoptosis were assessed by MTS assay and flow cytometry, respectively. To understand the mechanistic basis of EV induced alterations, next generation RNA sequencing was performed in control vs EV treated NCI-H660 cells on Illumina HiSeq platform. Significant targets were further validated by real time PCR and Western blot analyses. Results: Plant-derived nanovesicles reduced viability and induced apoptosis in NEPC cell lines. Genes involved in ECM-receptor interaction, focal adhesion, proteoglycans in cancer and small cell lung cancer genes were significantly impacted by these vesicles in NEPC cell line. Remarkably, nanovesicles led to significantly attenuated levels of key proneural transcription factors including ASCL1, BRN2 and SOX2. In addition, neuronal markers ENO2 and NCAM1 were downregulated suggesting that treatment with nanovesicles reverse the ‘cardinal’ genetic alterations that drive NEPC. Conclusions: Plant-derived nanovesicles can be employed as a novel treatment modality in neuroendocrine prostate cancer.
Anti-PD1 plus oncolytic virus as first-line treatment option for metastatic renal cell carcinomas.
Authors: Jee Soo Park, Myung Eun Lee, Won Sik Jang, Jongchan Kim, Namhee Lee, Keunhee Oh, Won Sik Ham
Journal: Journal of Clinical Oncology (2023)

675 Background: Although anti-programmed death (PD)1 and anti-cytotoxic T-cell lymphocyte (CTLA)-4 combination therapy is recommended as one of the first line treatment options for metastatic renal cell carcinoma (mRCC), immune checkpoint inhibitor (ICI) combination therapy leads to the increased immune-mediated adverse events (imAEs). Our group has reported the therapeutic potential of oncolytic virus, JX-594 in metastatic murine RCC model. In this study, we explored the effect of JX-594 plus anti-PD1 in comparison to the combination therapy of anti-PD1 and anti-CTLA-4. Methods: Early-stage and advanced-stage highly metastatic orthotopic murine RCC models developed by our group were used. Anti-PD1 with either JX-594 or anti-CTLA-4 were systemically injected through the peritoneum. Immunofluorescence analysis was performed to demonstrate the remodeling of the tumor immune microenvironment (TIME). Results: Both JX-594 plus anti-PD1 and ICI combination therapy significantly reduced primary tumor and metastatic tumor burden in lung and peritoneum compared to cytoreductive nephrectomy plus anti-PD1. For the early-stage and advanced-stage mRCC models, JX-594 plus anti-PD1 significantly decreased the primary tumor sizes and number of lung tumor nodules compared to ICI combination therapy only in the early-stage mRCC model ( P&lt;0.01), but not in advanced-stage mRCC model ( P=0.07). The therapeutic benefit was significantly increased when JX-594 and anti-PD1 was sequentially injected compared to when JX-594 and anti-PD1 was injected simultaneously ( P&lt;0.05). Notable imAEs were observed in 2/16 (12.5%) in ICI combination group, whereas no notable imAEs in JX-594 plus anti-PD1 group. JX-594 plus anti-PD1 induced changes in TIME of both early- and advanced-stage mRCC model. However, tumor-suppressing TIME was more notable in early-stage mRCC model, which increased tumor-infiltrating CD8+ T cells and tumor-suppressing M1 tumor-associated macrophages (TAM), and decreased tumor-promoting myeloid-derived suppressor cells (MDSCs) and M2 TAM. Conclusions: JX-594 plus anti-PD1 effectively reduced primary tumors and metastatic burdens similar to ICI combination therapy. Furthermore, imAEs significantly decreased in JX-594 plus anti-PD1 group, suggesting the potential benefit of JX-594 plus anti-PD1 for reserving ICI induced toxicities, especially by anti-CTLA-4.
Predictive accuracy of computer-generated padua nephrometry scores based on continuous variables compared with categorical computer-generated scores and human-generated scores in predicting oncologic and perioperative outcomes.
Authors: Tarik Benidir, Andrew Wood, Nour Abdallah, Erick M. Remer, Steven Campbell, Christopher J. Weight
Journal: Journal of Clinical Oncology (2023)

624 Background: The Preoperative Aspects and Dimensions Used for Anatomical Classification (PADUA) score is a validated predictor of a patient’s perioperative outcomes following partial nephrectomy. The use of a fully automated, unbiased and time sensitive PADUA scoring system is a novel concept that may help circumvent PADUA’s widespread adoptability. We sought to automate the scoring of preoperative computed tomography scans (CT) using a machine-learning-generated PADUA score (P-AI). In doing so, we aimed to compare P-AI’s ability to predict meaningful perioperative and oncologic outcomes as compared to human generated PADUA scores using both categorical (P-H) and continuous variables (P-AI+). Methods: 300 patients with pre-operative CT scans were identified from a cohort of 544 consecutive patients undergoing surgical extirpation for suspected renal cancer at a single institution. A deep neural network approach was used to automatically segment kidneys and tumors and geometric algorithms were developed to estimate each component of PADUA based on the segmented regions (P-AI). Tumors were also manually scored by medical personnel blinded to the P-AI (P-H). The ability of P-AI and P-AI+ to predict meaningful perioperative and oncologic outcomes was compared to P-H using logistic regression and receiver operating characteristics (ROC) curve analyses and areas under the curve (AUC). Results: Median age was 60 years, 40% were female. Median tumor size was 4.2 cm, 91.3% had malignant tumors, including 27% and 37% with high-stage and high-grade, respectively. Both P-AI and P-H were able to predict the need for partial nephrectomy (p &lt; 0.001). From an oncologic standpoint, P-AI and P-H were able to predict meaningful oncologic outcomes including the presence of malignancy, high grade and high stage disease (p &lt; 0.004) although the ROC curves were not different from one another). Interestingly, when each PADUA component was left as a continuous rather than ordinal variables (P-AI+), this automated continuous score was able to predict surgical type (AUC 0.88), presence of malignancy (AUC 0.67), indolent tumors (AUC 0.79) and high grade (AUC 0.77)/high stage disease (AUC 0.82), better than both P-AI and P-H. Conclusions: When viewed along a continuous spectrum, AI generated PADUA scores (P-AI+) yields predictive surgical and oncologic outcomes superior to both categorical AI and human generated PADUA scores. If nephrometry can be calculated automatically, there is no longer a need to simplify the equations and the use of an AI generated PADUA scoring system, provides a reliable estimate of meaningful outcomes in a manner that is time sensitive and superior to human expert evaluation. Further prospective work and reproducibility from other centers is encouraged.
Impact of race and payor status on patterns of utilization of partial and radical nephrectomy in patients with localized renal cell carcinoma (RCC).
Authors: Regina Barragan-Carrillo, Kai Dallas, Abhishek Tripathi, Ameish Govindarajan, Zeynep Busra Zengin, Luis A Meza, Errol James Philip, Daniela V. Castro, Alexander Chehrazi-Raffle, Neal Chawla, Joann Hsu, Nazli Dizman, Karyn Eilber, Cristiane Decat Bergerot, Sumanta Monty Pal
Journal: Journal of Clinical Oncology (2023)

614 Background: Racial minorities experience intersecting forms of marginalization and suffer significant healthcare disparities. Prospective trials have shown similar outcomes with partial and radical nephrectomy among patients with localized RCC (Van Poppel et al Eur Urol 2011), and multiple studies suggest increasing use of the former technique (Breau et al Can J Urol 2020). We hypothesize that patients from minority groups, as well as those with non-private insurance, will have less access to this specialized procedure and therefore have a higher rate of radical nephrectomy. Methods: We utilized the California Office of Statewide Health Planning and Development (OSHPD) database that collects information from all inpatient admissions, emergency room visits and inpatient/outpatient procedures in the state. All patients undergoing nephrectomy (both partial and radical) were identified from Jan 1, 2012 to Dec 31, 2018 using CPT and ICD-9/10 codes to identify patients. Demographic data was collected with specific attention to race and payor status. Univariate and multivariate analyses were conducted to determine the association between demographic data and procedure type. Results: In total, 31,093 patients were identified; 57% were males, with a mean age of 58 years. Among these, 16,142 (51.9%), 8,645 (27.8%), 2,795 (9.0%), 2,032 (6.5%) and 1,479 (4.8%) were characterized as White, Hispanic, Asian, Black and other, respectively. Partial nephrectomy and radical nephrectomy were performed in 15,840 (50.9%) and 15,253 (49.1%) of patients. By race, partial nephrectomy was performed in 8,576 (53.1%), 4,107 (47.5%), 1,286 (46.0%), 1,124 (55.3%) and 747 (50.5%) of White, Hispanic, Asian, Black and other patients, respectively (p&lt;0.001). Use of partial nephrectomy also differed among patients based on payor status, with rates of 6,800 (56.4%), 5,036 (43.9%), 1,817 (38.3%) and 2,187 (77.7%) among patients with private, Medicare, indigent coverage (e.g., MediCal or Medicaid) and other insurance, respectively (p&lt;0.001). On multivariate analysis controlling for age, gender, comorbidities and frailty, race was independently associated with type of nephrectomy procedure. Conclusions: Our study confirms that race and payor status may have an influence on utilization of partial versus radical nephrectomy, with the highest rate of partial nephrectomies among Whites and patients with private insurance. Although there are multiple potential confounders (e.g., latency of diagnosis and resulting tumor size/complexity), it is possible that access to care may be an important driver of these disparities.
Assessing treatment preferences among patients with advanced/metastatic renal cell carcinoma in the United States: A discrete choice experiment.
Authors: Moshe Chaim Ornstein, Lisa Rosenblatt, Flavia Ejzykowicz, Sarah Guttenplan, Viviana Del Tejo, Xin Yin, Kathleen M. Beusterien, deMauri S Mackie, Oliver Will, Grace Skiles, Marc DeCongelio, Steven S. Senglaub
Journal: Journal of Clinical Oncology (2023)

630 Background: The introduction of immunotherapies has changed the first-line treatment landscape for advanced/metastatic renal cell carcinoma (aRCC). This study examines patient preferences in this rapidly changing environment to better understand the tradeoffs patients with aRCC are willing to make when choosing treatment. Methods: Patients with self-reported aRCC in the United States completed an online, cross-sectional survey. A discrete choice experiment was used to assess preferences for attributes of aRCC treatments. Patients completed a series of choice tasks showing 2 treatment profiles that varied in 7 important attributes identified through literature and qualitative research: overall survival, progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), risk of adverse events, quality of life (QOL) changes, and treatment administration. Descriptive statistics were reported, and a hierarchical Bayesian logistic model was used to calculate preference weights. Relative importance estimates (mean ± standard error) were computed for each attribute; these represent the mean percentage of the variation in preferences explained by the attribute. Results: Survey results from a total of 299 patients were analyzed (male, 50%; mean age, 56 years). All 7 attributes were statistically significant for influencing the choice of treatment. Key attributes included treatment regimen convenience and QOL improvement, which ranked similarly to increasing survival time. Among the efficacy attributes, increasing survival time was most important, followed by ORR, PFS, and DOR. Reducing the risk of serious adverse events from 82% to 65% was prioritized after the efficacy parameters. Conclusions: Patients with aRCC highly value less burdensome treatment regimens and improved QoL in addition to improvement in survival. This highlights the need for a broader context beyond efficacy and safety when discussing treatment options with patients. Funding: This study was supported by Bristol Myers Squibb.
Utilization of local treatment modalities and surveillance in veterans with early stage renal cell carcinoma.
Authors: Abhishek Kumar, Joseph Kamel Salama, Matthew J Boyer
Journal: Journal of Clinical Oncology (2023)

643 Background: Surgery represents the standard treatment for early stage renal cell carcinoma (RCC). For older patients, especially those with comorbidities including chronic kidney disease (CKD), there have been efforts made to spare renal function. The objective of this study was to evaluate the disease and treatment characteristics of Veterans with early stage RCC. Methods: We used the national Veterans Affairs’ Corporate Data Warehouse (CDW) database to identify patients diagnosed between 2000-2018 with early stage (cT1-2N0M0) RCC. Laboratory and diagnosis data were used to calculate creatinine clearance and Charlson comorbidity score. Chronic kidney disease (CKD) was defined as creatinine clearance &lt; 60 milliliters per minute. The odds of receiving surveillance were evaluated with multivariable logistic regression. Results: Overall 19,555 Veterans with early stage RCC were included. The median age at diagnosis was 65, 90% range (48-82). 9,807 patients (50%) had at least 1 comorbidity and 4169 (21%) had multiple. Of 16,514 (84%) patients with available lab data, 1,359 (8%) patients had CKD. The treatments received were radical nephrectomy (RN) (N=4107, 21%), nephron sparing surgery (NSS) (N=5008, 26%), thermal ablation (N=489, 3%), and surveillance (N=9946, 51%). Compared to 2000-2010, from 2011-2018, there was a higher proportion of patients receiving NSS (29% vs. 20%, p &lt; 0.01) and a lower proportion receiving surveillance (49% vs. 54%, p &lt; 0.01). On multivariable logistic regression, predictors of receiving surveillance included older age (Odds Ratio [OR] 1.03 per year, p&lt;0.01), T1 disease (OR 1.18, 95% CI 1.08-1.28), increasing number of comorbidities (OR 1.12 per comorbidity point, 95% CI 1.08-1.16), or CKD (OR 1.25, 95% CI 1.12-1.41). Compared to creatinine clearance before diagnosis, the median change in creatinine clearance at least 1 year after diagnosis was -46 for RN, -9 for NSS, -8 for ablation, and -24 for surveillance (p&lt;0.01). Conclusions: A significant proportion of Veterans with early stage RCC undergo surveillance. Nephron sparing treatments are becoming increasingly common and are associated with more modest reductions in renal function than radical nephrectomy or surveillance. Further studies are warranted to assess the impact of surveillance on survival and cancer related outcomes.
Pelvic clinical node-positive prostate cancer: Impact of radiotherapy and nodal disease burden.
Authors: Tony Felefly, Alborz Jooya, Selena Laprade, Soumyajit Roy, Shawn Malone, Scott C. Morgan
Journal: Journal of Clinical Oncology (2023)

338 Background: The optimal management of pelvic clinical node-positive (cN1) prostate cancer remains controversial and randomized evidence for local therapy is lacking. Recent data suggests that common iliac nodal metastases (CIM), while technically constituting M1a disease, are more common than previously recognized and might carry a prognosis similar to that of cN1 disease when treated radically. In this context, we reviewed the experience at our center of treating cN1 prostate cancer, with or without CIM, focusing on the role of radiotherapy (RT) and measures of nodal disease burden. Methods: The study population consisted of men diagnosed between 2002 and 2018 with prostate cancer with cN1 disease and/or CIM and treated with androgen deprivation therapy and/or definitive local therapy. Outcomes of interest included overall survival (OS) and castration resistance-free survival (CRFS), which were estimated using the Kaplan-Meier method. Univariate and multivariate Cox regression were used to identify factors associated with OS and CRFS. In the subgroup of patients treated with RT, the association between a number of RT characteristics – including biologically effective dose (BED) to the prostate, use of elective pelvic nodal RT, and escalated dose (RT boost) to positive nodes – and OS was studied. Results: A total of 87 patients were included, of whom 14 had CIM and 68 received RT. Median follow-up was 110 months. On univariate analysis, RT was associated with improved OS (hazard ratio [HR] 0.28, 95% CI 0.14-0.55, p&lt;0.0005) and CRFS (HR 0.22, 95% CI 0.12-0.41, p&lt;0.0005). Median OS in patients receiving RT was 134.9 months versus 63.1 months in those not receiving RT. Receipt of RT remained significantly associated with OS on multivariate analysis (HR 0.12, 95% CI 0.05-0.31, p&lt;0.001). Biopsy Gleason score 10 and presence of &gt;2 positive lymph nodes were associated with worse OS while presence of CIM was not associated with OS. In patients treated with RT, increasing BED to the prostate was associated with improved OS (HR 0.73 per 10 Gy increase, 95% CI 0.54-0.97, p=0.03) while use of elective pelvic nodal RT and use of an RT boost to positive nodes were not associated with OS. Conclusions: This is the first cohort to evaluate the impact of RT in pelvic clinical node-positive prostate cancer that includes CIM. Receipt of RT was associated with improved oncologic outcomes. The number of positive pelvic nodes, but not their common iliac location, was prognostic and warrants further investigation in a larger dataset.